This application is a 371 of PCT/DK98/00388 filed Sep. 10 1998,
The present invention relates to an oral pharmaceutical modified release multiple-units composition for the administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti-inflammatory drug substance (in the following abbreviated xe2x80x9can NSAID substancexe2x80x9d) to obtain both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time. The modified release multiple-units composition comprises at least two fractions of multiple units such as a first and a second fraction. The first fraction comprises individual units which are designed to quickly release the drug substance and the second fraction comprises individual units which are designed to slowly release the drug substance to enable a delayed and extended release of the drug substance. Typically, the second fraction comprises multiple units which are coated with a sustained release coating designed to release the drug substance in such a manner that the maintenance of a therapeutically active plasma concentration for a relatively long period of time are obtained. By suitable adjustment of the release pattern of the at least first and second fraction a composition is obtained which is adapted to once- or twice-a-day administration.
Drug levels can be maintained above the lower level of the therapeutic plasma concentration for longer periods of time by giving larger doses of conventionally formulated dosage forms. However, it is not a suitable approach to increase dosage as such doses may produce toxic and undesired high drug levels. Alternatively, another approach is to administer a drug at certain intervals of time, resulting in oscillating drug levels, the so-called peak and valley effect. This approach is generally associated with several potential problems, such as a large peak (toxic effect) and valley (non-active drug level) effect, and a lack of patient compliance leading to drug therapy inefficiency or failure. If, however, the plasma concentration is kept constant over the therapeutic level using conventional tablets, an unacceptably high daily dosage is required if the active substance is not administered very frequently. Controlled release compositions are known which are designed to rapidly release a fraction of a total drug dose. This loading dose is an amount of a drug which will provide a desired pharmacological response as fast as possible according to the biopharmaceutical properties of the drug substance. Generally, such compositions in some more or less sophisticated manner are composed of a sustained release part and a part which either contains a free amount of the drug substance or it releases the drug substance in the same manner as if the drug substance had been formulated as a plain formulation (e.g. in the form of normal tablets or granulates). Such compositions which initially release a burst of a therapeutic agent and then release the agent at an essentially constant rate are described, e.g., in WO 95/14460 (Euroceltique S. A.) published on Jun. 1, 1995. The composition described therein relates to a sustained release opioid formulation comprising a plurality of substrates comprising the active ingredient in a sustained release matrix or coated with a sustained release coating comprising a retardant material. The sustained release beads are then coated with an opioid in immediate release form or, in the case the composition is in the form of a gelatine capsule, an amount of free opioid (i.e. the opioid is included as such and has not been processed into a specific formulation e.g. by means of pharmaceutically acceptable excipients) is incorporated into the gelatin capsule via inclusion of a sufficient amount of opioid within the capsule. In a further alternative, the gelatine capsule itself is coated with an immediate release layer of the opioid.
Generally, the rationale which lies behind the kind of compositions which have been described to enable an immediate release of a drug substance as well as a sustained release of the drug substance is to combine a traditional formulation approach (such as, e.g., i) plain tablets which have a disintegration time in water of at the most about 15 min for uncoated tablets, cf. Ph. Eur. (the requirements for coated tablets or capsules are at the most 30 min), ii) a traditionally formulated granulate or iii) loose powder of the drug substance itself) with a controlled release approach. By doing so the immediate release part of the composition is intended to release the drug substance in a manner which corresponds to a plain tablet formulation or the like and the term xe2x80x9cimmediatexe2x80x9d is in such a context intended to denote that the release of the drug substance is faster than the release from a sustained release composition. The immediate release is in no way intended to be faster than that of a traditional or plain composition.
Especially in those cases where the drug substance has a low solubility in an acidic medium having a pH of from about 1 to about 3, i.e. a pH corresponding to the pH in the stomach, the traditional formulation approach will lead to a pharmaceutical composition which has a suitable fast disintegration time but not necessarily a suitable dissolution rate of the drug substance under acidic conditions, i.e. a plain tablet will rapidly disintegrate into granules but the dissolution of the drug substance from the composition and/or the disintegrated composition under acidic conditions may be unsuitable low due to the solubility properties of the drug substance itself. The availability of a drug substance with respect to absorption, i.e. entrance into the circulatory system, is dependant on the presence of the drug substance on dissolved form as it is generally accepted that only dissolved substances are capable of passing the mucous membranes in the gastro-intestinal tract. Therefore, it is important that the dissolution of the drug substance is suitably fast even under acidic conditions in order to enable an initial absorption already from the stomach so that a true fast or immediate therapeutic response is obtainable. Furthermore, if a drug substancexe2x80x94dependent on pH can exist on un-ionized as well as ionized form (e.g. acetyl salicylic acid which at an acid pH below its pKa value predominantly is present on an unloaded, i.e. un-ionized form, whereas at a pH above its pKa value predominantly is present on ionized form). For drug substances which are weak acids it is very important to ensure a proper bioavailability of the drug substance already under acidic conditions in order to achieve a true rapid therapeutic effect. However, the various approaches disclosed with respect to achievement of a combination of a rapid and a sustained effect (e.g. in the publications mentioned above) do not seem to take the above-mentioned factors into account and, hence, there is a need for developing compositions which enable a true rapid onset of the therapeutic effect as well as a sustained effect. To this end, we have especially focused on compositions comprising a drug substance suitable for use in situations where a rapid effect is needed but also in situations where an extended effect is desirable in order to develop compositions suitable for administration less frequent than compositions on the market today, more specifically to enable administration on a once or twice daily basis. Examples of suitable drug substances are, e.g., substances which have a pain relief effect. More specifically, interesting drug substances are those belonging to the class of drug substances normally denoted NSAIDs or NSAID substances.
In EP-A-0 438 249A1 (ELAN Corporation P.L.C.) is given another example of a composition which has been designed to release naproxen immediately and sustained. However, as shown in Example 18 herein, the so-called immediate release of naproxen does not take place under acidic conditions, i.e. conditions prevailing in the stomach. Accordingly, such a composition is not within the scope of the present application.
As will be apparent from the following the present inventors have developed a composition in multiple-units form for a quick release as well and an delayed and extended release.
Multiple-units formulation techniques according to the invention aim at a modified release of a drug substance in a predetermined pattern to control the peak plasma concentration without affecting the bioavailability, i.e. the extent of drug availability. The release of an NSAID substance from a composition according to the present invention is controlled in a very flexible manner as described below. Many advantages are obtained, e.g., the frequency of undesirable side effects may be reduced, and due to the control of the time it takes to obtain the peak plasma concentration and the prolongation of the time at the therapeutically active plasma concentration, the frequency of the administration may be reduced to a dosage taken only twice or once a day. This also serves to improve patient compliance. A further advantage of the modified release multiple-units dosage form is that high local concentrations of the active substance in the gastro-intestinal system are avoided, due to the units being distributed freely throughout the gastrointestinal tract, independent of gastric emptying.
Moreover, patients suffering from pain and/or inflammatory conditions and/or related conditions very often require high daily dosages of NSAID substances. If such high dosage of an NSAID substance should be given only once a day, the release from the dosage form must be safe, predictable and reliable. The composition should also be very storage stable because an immediate release due to accidental damaging of e.g. the coating or capsule of a high dosage form may result in undesired high plasma concentrations, so-called dose dumping, which could cause undesired side effects. Furthermore, from a technical point of view, the release rate and the release pattern of the active drug substance from the composition should not significantly change during the shelf-life of the composition. Even a minor change in the release rate and/or release pattern may have a significant impact on the in vivo performance of the composition.
By use of a coated multiple unit dosage form, the risk of dose dumping due to e.g. rupturing of a coating is reduced because the amount of active ingredient in each coated unit is negligible.
The compositions according to the present invention are intended to reduce or essentially eliminate problems identified with other kind of compositions intended for administration once daily. Thus, a major disadvantage of the once-a-day treatment in the art may be a low plasma concentration at the end of the dosing period and thereby the lack of therapeutic response. As the treatment of pain and/or inflammatory conditions and/or related conditions, is a balance of therapeutic effect on the one hand and the risk of side effects on the other hand, e.g. due to accumulation of drug, the dosage interval is generally calculated so that the drug concentration is substantially decreased at the time of intake of the next dosage. Accordingly, the patient will very often suffer from disease symptoms before the drug concentration subsequent to the next dosage has reached the therapeutic level. In addition, it should be noted that in the treatment of pain and/or inflammatory conditions and/or related conditions, relatively higher dosages, corresponding to a relatively higher peak concentration, are often needed in case the symptoms break through. Accordingly, a relatively higher initial plasma concentration of an NSAID substance may be necessary compared to the plasma concentration at steady state.
However, to the best of our knowledge no oral non-steroid anti-inflammatory modified release pharmaceutical composition has been disclosed which at the same time can be produced in an easy, cheap and reliable manner and which provides a suitable profile for release of active substance (under acidic, neutral and basic conditions) resulting in an extended period of action so that the inflammatory condition is both rapidly alleviated after administration and avoided for a period of about 12 to 24 hours.
Therefore, there is a need for developing a composition comprising a non-steroid anti-inflammatory drug substance permitting the administration of dosages only once or twice a day in a safe and reliable manner, and which is easy to produce, preferably involving conventional production methods and as few production steps as possible. It is also important that an NSAID composition for daily administration comprises the active ingredient in such a way that the composition has a reliable dissolution rate since a change in the dissolution pattern of the NSAID substance could be disadvantageous for the patient.
The purpose of the present invention is to provide an oral modified release multiple-units composition for administration of a daily dosage of an NSAID substance in a dosage form which only requires administration at the most twice daily, preferably once daily, and which overcomes the drawbacks of hitherto suggested formulations of modified release compositions containing an NSAID substance in that the dosage form both provides a substantially fast release from a first fraction comprising multiple units and a delayed and extended release from a second fraction of multiple units of the NSAID substance whereby alleviation of symptoms is achieved shortly after administration and is maintained for at least 12 hours, preferably 24 hours after administration.
A further aspect of the invention is to provide a process for the preparation of a composition of an oral pharmaceutical modified release multiple-units composition containing an NSAID substance, and in addition, a method for treating patients with a composition according to the invention whereby the interval between each administration is increased to about 12-24 hours.
Accordingly, the present invention relates to an oral pharmaceutical modified release multiple-units composition in unit dosage form for administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti-inflammatory drug substance (an NSAID substance), a unit dosage form comprising two NSAID-containing fractions,
i) a first NSAID-containing fraction of multiple-units for quick release of the NSAID substance, and
ii) a second NSAID-containing fraction of multiple-units for extended release of the NSAID substance,
the first fraction whichxe2x80x94when subjected to dissolution method II as defined herein employing 0.07 N HCl as dissolution mediumxe2x80x94releases at least 50% w/w of the NSAID substance present in the fraction within the first 20 min of the test,
the second fraction being in the form of coated delayed release multiple-units for extended release of the NSAID substance.
The present invention also relates to a composition for the administration of a therapeutically and/or prophylactically effective amount of an NSAID substance to obtain both a relatively fast onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time, a unit dosage of the composition comprising at least two fractions as follows:
a first fraction of quick release multiple-units for relatively quick release in vivo of an NSAID substance to obtain a therapeutically and/or prophylactically active plasma concentration within a relatively short period of time, and
a second fraction of coated modified release multiple-units for extended release in vivo of an NSAID substance to maintain a therapeutically and/or prophylactically active plasma concentration in order to enable dosing once or twice daily,
the formulation of the first and the second fractions, with respect to release therefrom and with respect to the ratio between the first and the second fraction in the unit dosage, being adapted so as to obtain:
a relative fast in vitro release of the NSAID substance from the first fraction of quick release multiple-units, as measured by the dissolution method 11 as defined herein, an extended in vitro release of the NSAID substance from the second fraction of extended release multiple-units relative to the in vitro release of the first fraction of the NSAID substance, as measured by the dissolution method III as defined herein, the quick release and the extended in vitro release being adapted so that the first fraction is substantially released when the release from the second fraction is initiated corresponding to at least 50% w/w release of the NSAID substance contained in the
first fraction at the time when at the most about 15% w/w such as, e.g., at the most about 10% w/w or at the most about 5% w/w of the NSAID substance contained in the second fraction is released as measured by the dissolution method III as defined herein.
It should be noted that the dissolution methods mentioned above and throughout the specification of course may be adjusted to specific drug substances and in some cases replaced with other dissolution methods. However, the requirements claimed herein should still be fulfilled.
The modified release multiple-units dosage forms of the present invention achieve and maintain therapeutic plasma concentrations for a prolonged period of time. In order to achieve the relatively fast absorption for the first fraction it requires that NSAID substances dissolve in the stomach (cf. the discussion above). Since the solubility of an NSAID substance such as, e.g., lornoxicam is  less than 1 mg/100 ml in 0.1 N HCl (aqueous solution of 0.1 N hydrochloric acid) the present inventors have found that incorporation such an NSAID substance in free form or in the form of a traditional formulation does not give the desired quick release under acidic conditions to enable a fast onset of the therapeutic effect in vivo. However, and as it will be discussed in detail below, a quick release of an NSAID substance (which is a weak acid or has a very low solubility under acidic conditions) takes place under acidic conditions provided that the drug substance is presented in a formulation wherein specific means has been used in order to manipulate the release rate so that the release becomes much faster than from a traditional composition. Thus, in contrast to the prior art composition in which focus only has been on the extended release rate part of the compositions and on the possibility of changing the release from this part, the present inventors have found it necessary to adjust the release rate from both the fast and the slow release part of a composition when the NSAID substance either has a very low solubility in 0.1 N hydrochloric acid or has a pKa below about 5.5 such as, e.g., about 4-5. Thus, both the fast release fraction and the delayed release fraction must be manipulated with respect to release in order to achieve a suitable overall release rate.
The first fraction of the composition constitutes the quick releasing part of the composition whereas the second fraction of the composition constitutes the delayed and extended release part of the composition. In the first fraction, the release rate is primarily governed by the formulation of the fraction, i.e. the ingredients employed and the processing of the ingredients to obtain the first fraction (cf. Danish Patent Application filed on Sep. 10, 1998 in the name of Nycomed Danmark). In those cases, where a coating is present on the units of the first fraction, the coating may of course also contribute to the control of the release of the active drug substance from the first fraction. In the second fraction, the release rate is primarily governed by the constitution and thickness of a controlled release membrane which are applied on pellet cores (also denoted xe2x80x9cpelletsxe2x80x9d).
The delayed and extended fraction is based on the application of a release controlling membrane. The release is being controlled by the membrane which makes the formulation much more robust and easier to manipulate and manufacture. Ideally there is no release controlling effect from the uncoated units of the second fraction, i.e. the uncoated multiple-units of the second fraction do not significantly contribute to any control of the extended release of the active drug substance but the uncoated multiple-units merely release the active drug substance freely without any significant retardation.
The modified release multiple-units dosage forms of the present invention achieve and maintain therapeutic levels and, at the same time, reduces the risks for any side effect, which are believed to be associated with high blood levels of NSAID substances. Furthermore, the delayed or extended release properties of the coating applied on the second fraction of the multiple-units dosage forms of the present invention are unaffected by the pH in the gastro-intestinal tract.
The first fraction of the multiple-units dosage form of the invention may also be in the form of coated multiple-units provided that the release rate of such a fraction is so fast in the dissolution medium employed in dissolution method II described herein that at least 50% w/w of the total dose of the first fraction is released within the first 20 min.
When a coating is present on the multiple-units of the first fraction then it could advantageous be of the same kind as an outer coating on the multiple-units of the second fraction. The employment of the same kind of coating for each fraction may be performed with substantially identical procedures and materials and the production cost can be kept at a low level.
Accordingly, the present invention relates to an oral pharmaceutical modified release multiple-units composition in unit dosage form for administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti-inflammatory drug substance (an NSAID substance), a unit dosage form comprising two NSAID-containing fractions,
i) a first NSAID-containing fraction of multiple-units for quick release of the NSAID substance, and
ii) a second NSAID-containing fraction of multiple-units for extended release of the NSAID substance,
the first fraction whichxe2x80x94when subjected to dissolution method 11 as defined herein employing 0.07 N HCl as dissolution mediumxe2x80x94releases at least 50% w/w of the NSAID substance present in the fraction within the first 20 min of the test,
the second fraction being in the form of coated delayed release multiple units for extended release of the NSAID substance.
As discussed above it is very important to secure that the release pattern of the active drug substance contained in the composition is suitable for a composition for administration once or twice daily. The employment of at least two different fractions of multiple-units gives very flexible formulation parameters. Thus, it is possible to vary i) the percentage of the total dose of the NSAID substance contained in each fraction and ii) the weight ratio between the different fractions. The system (i.e. formulation concept) is therefore very suitable to not only one specific drug substance but can within certain limits be applied on a class or many classes of active drug substances once the target release profile has been determined. Of course, a change from one active drug substance to another active drug substance may give rise to certain adjustments of the constitution of the individual fractions to the specific substance. In the following is given a discussion of how to determine a target profile for an active drug substance and the release requirements generally applicable for the group of active drug substances belonging to the non-steroid anti-inflammatory drug substances.
As described in the following, a target release profile can be designed for any NSAID substance. In the following the target release profile for a selected NSAID substance is described, namely lornoxicam.
Based on the knowledge of the pharmacokinetics of lornoxicam and a study performed by us employing a plain tablet and a solution (Hitzenberger G, Radhofer-Welte S, Takacs F, Rosenow D.: Pharmacokinetics of lornoxicam in man, Postgrad. Med. J. 1990, 66, pp S22-S26), a target in vivo profile for a once daily product has been estimated (FIG. 1).
The presumptions made in estimating this target profile were:
i) a double peak and an effective concentration for 24 hours are desired from a therapeutic point of view (i.e. plasma lornoxicam concentrations at 24 hours should be similar to the plasma concentration obtained 8-12 hours after administration of half the dose in the form of a plain tablet),
ii) that the first fraction of the composition should have an absorption rate similar to or faster than that of plain tablets
iii) that the peak concentration should not be higher than the peak concentration observed after administration of half the dose in the form of a plain tablet, and
iv) that the second peak should appear about 5-6 hours after dosing.
A person skilled in the art is capable of determining the actual values with respect to the above-mentioned provisions and based on such values perform any necessary correction to the estimated profile (target profile).
The estimated target plasma profile as well as the profile from plain tablets have been deconvoluted with plasma concentrations from an oral solution to give an estimated in vivo dissolution profile (FIG. 2). All data were normalised to a dose of 16 mg. In the deconvolution a time interval of 0.5 hours was employed (cf. Langenbucher F., and H. Mxc3x6ller: Correlation of in vitro drug release with in vivo response kinetics. Part I: Mathematical treatment of time functions. Pharm. Ind. 1983, 45, pp 623-8 and Langenbucher F. and H. Mxc3x6ller: Correlation of in vitro drug release with in vivo response kinetics. Part II: Use of function parameters. Pharm. Ind. 1983, 45, pp 629-33).
The presumptions in making this deconvolution were that the daily dose of lornoxicam is the same irrespective of whether a once daily composition or a plain tablet or a solution were administered,
The estimated in vivo dissolution profile for a once daily product can be used as the target in vitro profile for the combination of a fast or quick release fraction (i.e. the first fraction) and an extended or slow release fraction (i.e. the second fraction, coated pellets). The estimated in vivo dissolution profile for the once daily composition can be used as the target in vitro profile, when performing the dissolution tests in vitro with 1 hour in 0.1 N HCl and then shift to phosphate buffer pH 7.3 or 7.4 (dissolution methods III or IV described herein). This knowledge has been utilized in order to arrive at the dissolution requirements described in the following.
The presumptions made in using the estimated in vivo profile as target for in vitro profile were:
i) that a plain tablet will remain in the stomach for about 1 hour before a passage into the intestine takes place (estimated from the difference in Tmax between the solution (0.5 hours) and the plain tablet (1.5 hour),
ii) that the correlation between the in vitro dissolution and the in vivo dissolution is a 1:1 correlation, and
iii) that lornoxicam is absorbed through the whole gastrointestinal tract (including colon) in order not to loose any amount of active drug substance ready for absorption into the circulatory system.
Before going into detail with respect to the release requirement to the first fraction, the second fraction and the composition in its final form, in the following is given details with respect to the target release profile for a once daily lornoxicam composition. The profile has been estimated as described above.
Taget release in vivo profile (corresponds to target release profile in vitro employing dissolution methods III or IV as described herein):
As apparent from the above, the first fraction must release the active drug substance quickly in 0.1 N HCl or in the dissolution medium employed in dissolution method II described herein, i.e. under conditions simulating the conditions in the stomach and under these conditions the second fraction does not release any significant amount of the active drug substance. In this connection it is important to note that even if the second fractions does not release any significant amount of the active substance within the first 20 min or 1 hours under acidic conditions, then the controlled release coating is not necessarily designed as an enteric coating, i.e. a coating which is insoluble at acidic pH and soluble at neutral/basic pH. The compositions according to the invention exemplified in the experimental section are examples on compositions wherein the controlled release coating of the second fractions is not an enteric coating. Furthermore, application of an enteric coating on e.g. pellets would not lead to an extended release of an active drug substance. The release will of course be delayed (no release under acidic conditions) but as the pH becomes neutral and alkaline, then the enteric coating dissolves, i.e. there is no membrane left to control the release.
Notably, the release of the active drug substance from the first fraction is at least 55% w/w such as, e.g., at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w or at least about 80% w/w of the total NSAID substance present in the first fraction within the first 20 min of the test, i.e. the dissolution method II (pH corresponding to 0.07 N HCl) as defined in the experimental section.
In one embodiment the composition may comprise modified release multiple units wherein the in vitro dissolution characteristics of the first fraction of quick release multiple-units within 0.5 hour provides a release as defined by the dissolution methods II as described herein of at least about 50% w/w, at least about 60% w/w, at least about 70% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w or at least about 95% w/w calculated on the total amount of active drug substance contained in the first fraction.
In addition, the composition-may comprise modified release multiple units wherein the in vitro dissolution characteristics of the first fraction of quick release multiple units within 1 hour provides a release as defined by the dissolution methods II described herein of at least about 50% w/w, such as, e.g., at least about 60% w/w, at least about 70% w/w, at least about 80% w/w, at least about 85%, at least about 90% w/w or at least about 95% w/w calculated on the total amount of active drug substance in the first fraction.
As apparent from the discussion above, the overall release characteristics with respect to release of the active drug substance from the final composition are composed of the release characteristics of the first and the second fraction of multiple-units, respectively. With regard to compositions containing an NSAID substance intended for administration once or twice daily, the present inventors have found that the release characteristics of the second fractions most suitably should have the following order of magnitude provided that the release characteristics of the first fraction are as discussed above.
Accordingly, the in vitro dissolution characteristics of the second fraction of extended release multiple units may in one embodiment within 1 hour provide a release as defined by the dissolution method III described herein in the range of 0%-about 30% w/w, such as, e.g., in the range of 0%-about 20% w/w, in the range of 0%-about 10% w/w such as about 5% w/w calculated on the total amount of active drug substance in the second fraction.
Furthermore, the in vitro dissolution characteristics of the second fraction of extended release multiple units may within 3 hours provide a release as defined by the dissolution method III described herein in the range of about 10%-70% w/w, such as, e.g., in the range of about 10%-60% w/w, in the range of about 12%-50% w/w, in the range of 14%-45% w/w, in the range of about 15%-30% w/w, in the range of about 15%-20% w/w such as, e.g., about 17% w/w of the NSAID substance.
Within 6 hours, the in vitro dissolution characteristics of the second fraction of extended release multiple units may provide a release as defined by the dissolution method III described herein in the range of about 35%-95% w/w, such as, e.g., in the range of about 50%-90% w/w, in the range of about 50%-80% w/w, in the range of 50%-75% w/w, in the range of about 50%-60% w/w, in the range of about 53%-59% w/w such as, e.g. about 56% w/w of the NSAID substance.
In addition, within 9 hours the in vitro dissolution characteristics of the second fraction of extended release multiple units may provide a release as defined by the dissolution method III described herein in the range of about 50%-100% w/w, such as, e.g., in the range of about 60%-98% w/w, in the range of about 65%-95% w/w, in the range of about 70%-90% w/w, in the range of about 70%-80% w/w such as, e.g., about 76% w/w of the NSAID substance.
To ensure that the final composition has a proper constitution with respect to the weight amount of first fraction relative to the amount of second fraction, the in vitro dissolution characteristics of the first and second fractions are in one embodiment adapted so that the first fraction is substantially released when the release from the second fraction is initiated, corresponding to at least 50% w/w release of the first fraction at the time at the most about 15% w/w such as, e.g., at the most about 10% or at the most about 5% w/w of the second fraction is released, as measured by the dissolution method III described herein. In addition, the in vitro dissolution characteristics of the first and second fractions in the same or a second embodiment as mentioned above are adapted so that the first fraction is substantially released when the release from the second fraction is initiated, corresponding to at least 70% w/w release of the first fraction at the time at the most about 20% w/w such as, e.g., at the most 15% w/w or at the most about 10% wow of the second fraction is released, as measured by the dissolution method III described herein.
Apart from the requirements to the individual fractions contained in the composition it is of course of utmost importance to ensure that the composition in its final form has in vitro dissolution characteristics which give evidence for a suitable in vivo behaviour, i.e. a fast onset of the effect together with an extended release of the active drug substance to ensure a therapeutic and/or prophylactic effect upon administration once or twice daily.
The two fractions of multiple units may be selected, with respect to the release from each fraction and the ratio between the two fractions, so that the in vitro dissolution characteristics of the composition within 1 hour provide a release of the NSAID substance in the first and second fractions in the range of from about 5% w/w to about 50% w/w, such as, e.g., in the range of from about 5% w/w to about 45% w/w, in the range of from about 15% w/w to about 40% w/w, in the range of from about 20% w/w to about 35% w/w such as about 29% w/w, as defined by the dissolution method III described herein.
In addition, the two fractions of multiple units may be selected, with respect to the release from each fraction and the ratio between the two fractions, so that the in vitro dissolution characteristics of the composition within 3 hours provide a release as defined by the dissolution method III described herein in the range of from about 20% w/w to about 80% w/w, such as, e.g., in the range of from about 25% w/w to about 70% w/w, the range of from about 30% w/w to about 60% w/w, in the range of from 35% w/w to about 55% w/w such as about 42% w/w.
In an additional aspect, the two fractions of multiple units may be selected, with respect to the release from each fraction and the ratio between the two fractions, so that the in vitro dissolution characteristics of the composition within 6 hours provide a release as defined by the dissolution method III described herein in the range of from about 40% w/w to about 98% w/w, such as, e.g., in the range of from about 50% w/w to about 95% w/w, in the range of from about 60% w/w to about 90% w/w, in the range of from about 60% w/w to about 85% w/w, in the range of from about 60% to about 83% such as about 69-70% w/w.
Furthermore, the two fractions of multiple units may be selected, with respect to the release from each fraction and the ratio between the two fractions, so that the in vitro dissolution characteristics of the composition within 9 hours provide a release as defined by the dissolution method III described herein in the range of from about 50% w/w to about 100% w/w, such as, e.g., in the range of from about 60% w/w to about 99% w/w, in the range of from about 70% w/w to about 98% w/w, in the range of from about 70% w/w to about 97% w/w, in the range of from about 75% w/w to about 96% w/w, such as in the range of from about 80% w/w to about 96%, such as about 80-85% w/w.
In a preferred embodiment, the composition fulfils the above criteria with respect to the dissolution characteristics of the composition in the full time span mentioned.
The percentage of NSAID substance in the first fraction is in the range of about 5%-50% w/w such as, e.g., in the range of about 10%-45% w/w, in the range of about 15%-45% w/w, in the range of about 20%-40% w/w, in the range of about 25%-40% w/w, in the range of about 25%-35% w/w such as, e.g., about 30% w/w, calculated on the total amount of NSAID substance in the composition.
The percentage of NSAID substance in the second fraction is in the range of about 30%-99% w/w such as, e.g. in the range of about 40%-98% w/w, in the range of about 45%-95% w/w, in the range of about 50%-95% w/w, in the range of about 55%-85% w/w, in the range of about 60%-80% w/w, in the range of about 60%-75% w/w, in the range of abut 65%-75% w/w such as, e.g., about 70% w/w, calculated on the total amount of NSAID substance in the composition.
In a preferred embodiment, the multiple units of the second and, when appropriate, the first fraction are coated, cross-sectionally substantially homogeneous pellets.
It is preferred that the multiple units of the first fraction result in a peak plasma concentration of the NSAID substance which is substantially the same as the peak concentration resulting from the second fraction. As the peak plasma concentration of the second fraction is adapted so that plasma concentration has a prolonged character due to the dissolution characteristics of the fraction described herein, the peak of this second fraction should preferably substantially represent the upper level of the therapeutic plasma concentration. In a preferred embodiment, the plasma concentration level is of such a size that no NSAID substance is in excess.
Since the total amount of NSAID substance contained in the first fraction is balanced compared to the total amount of NSAID substance in the composition, a peak plasma concentration of NSAID substance derived from the first fraction which is higher than the peak concentration resulting from the second fraction does not necessarily represent a substantial waste of the NSAID substance.
However, unless the patient suffers from heavy breakthrough symptoms wherein a higher plasma concentration than the plasma concentration for maintaining symptom alleviation often seems to be needed, the concentrations obtained from the first fraction should not exceed the peak from the second fraction.
Even in the circumstances wherein the peak of the first fraction is preferably higher than the peak from the second fraction, unsuitable high plasma concentrations (within the toxic level) derived from the first fraction may easily be avoided by adjusting the amount of active drug substance contained in the first fraction.
In another embodiment, e.g. in the circumstances wherein the patient is well treated by administration once or twice a day with a composition according to the invention, the first fraction may be adapted so that it results in a peak plasma concentration of the NSAID substance which is lower than the peak concentration resulting from the second fraction. This would not necessarily result in breakthrough symptoms as the NSAID substance remaining in the plasma from the previous dosage administered may contribute to maintaining the plasma concentration sufficiently high until the second fraction of the composition is released. In other cases, the daily dosage may be administered at a suitable time of the day when the patient has experienced less need for the NSAID, e.g. before bedtime.
Accordingly, an important aspect of the invention is an embodiment wherein the first fraction results in a therapeutically active plasma concentration of the NSAID substance until the delayed release of an NSAID substance from the second fraction of modified release multiple units contributes to the maintenance of a therapeutically active plasma concentration of the NSAID substance.
As discussed above, the multiple-units of the first fraction may be in the form of uncoated pellet cores, coated pellet cores, granules, a granulate or small plain tablets provided that the requirements with respect to release of active drug substance in 0.1 N HCl and under conditions as those described under dissolution method II herein are fulfilled. In those cases, where the first fraction is in the form of coated pellets, the time lag of the release from the second fraction relative to the first fraction may be obtained by a modified release coating of the second fraction which is present in a range of about 2%-80% such as, e.g., about 2%-70%, about 2-60%, about 3-50%, about 3-40%, about 4-30%, about 5-20% or about 2-5%, relative to the uncoated unit.
It is also preferred that the modified release coating of the fraction(s) is substantially water-insoluble, but water-diffusible and substantially pH-independent which will facilitate an absorption independent of the presence of food in the stomach.
In general, the dosage of the active drug substance present in a composition according to the invention depends inter alia on the specific drug substance, the age and condition of the patient and of the disease to be treated.
Compositions according to the invention intended for once daily administration will generally contain a daily dose of the active drug substance whereas compositions according to the invention intended for twice daily administrations will generally contain half the daily dose of the active drug substance. However, the daily dose may be divided into several dosage forms.
In the following is listed the recommended daily doses for selected NSAID substances.
Aceclofenac: 200 mg
Diclofenac: 100 mg
Etodolac: 400 mg
Fenbufen: 900 mg
Fenoprofen: 1.5
Flurbiprofen: 200 mg
Ibuprofen: 1.6 g
Indometacin: 100 mg
Ketoprofen: 200 mg
Meloxicam: 15 mg
Nabumeton: 1 g
Naproxen: 750 mg
Piroxicam: 20 mg
Sulindac: 300 mg
Tenoxicam: 20 mg
Tiaprofenic acid: 600 mg
Tolfenamic acid: 400 mg
Tolmetin: 800 mg
The amount of an NSAID substance of the modified release multiple-units composition according to the invention may be selected so that is corresponds to about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 16 mg, 20 mg, 24 mg, 25 mg, 30 mg, 3 mg, 50 mg, 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 1.1 g, 1.2 g, 1.3 g or 1.6 g of NSAID substance which are dosages generally known in the art. However, the composition according to the invention preferably comprises an amount of an NSAID substance which is a daily therapeutically effective amount of the NSAID substance.
Generally, with conventional dosage forms such as plain tablets comprising an NSAID substance, it is not always possible to obtain identical release profiles when different dosages are administered together as the load of active ingredient may differ depending on the size of the tablet. The release profile for 100 mg given in a single dosage may thus differ from 100 mg given as 5 dosages comprising 20 mg each. Not even with the commercially available modified release dosage forms, a substantially identical release profile within the different dosages is always observed.
With a composition according to the present invention, it is now possible to administer different dosages with identical release profiles (cf. results reported in the experimental section). For example, if each modified release multiple-units composition according to the invention is prepared with the same type of multiple units of the first and second fractions and in the same ratios, each of the dosage forms may be administered together to obtain any desired total dosage without altering the overall release profile from the total dosage. Accordingly, reliable and predictable plasma concentrations during the complete time span between administration may be obtained independently of the total dosage.
Therefore, a further advantage of the composition according to the invention is that the composition may be produced in different series of dosage forms of e.g. 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg etc., each of the series having individual properties resulting from the design of modified release of the first and second fractions as well as from the ratio between the fractions. Any desired total dosage can then be selected from the relevant dosage forms within each of the series.
The preferred dosage form according to the invention is in the form of a capsule, tablet, sachet etc. The size of the dosage form is adapted to the amount of the NSAID substance of the composition.
The above suggested dosage amounts should not be regarded as a limitation of the scope of the invention as it is obvious for the skilled person that any desired amount of the NSAID substance may be applied and is only limited by the size of the composition and the type of the NSAID substance.
The overall goal of the present invention is to provide a composition in unit dosage form for the administration of a therapeutically effective amount of an NSAID substance once a day. However, as some patients may still need to, or prefer to, receive administration twice a day, the invention should not be limited to a once-a-day composition as long as each of the unit dosage forms fulfils the criteria with respect to the dissolution mentioned above.
In a further aspect, the invention relates to a process for the preparation of an oral pharmaceutical modified release composition, the process comprising incorporating into the unit dosage at least two fractions as follows:
a first fraction of quick release multiple-units for relatively quick release in vivo of an NSAID substance to obtain a therapeutically or prophylactically active plasma concentration within a relatively short period of time, and a second fraction of coated extended release multiple-units for extended release in vivo of an NSAID substance to maintain a therapeutically active plasma concentration in order to enable dosing once or twice daily,
the formulation of the first and the second fractions, with respect to release therefrom and with respect to the ratio between the first and the second fraction in the unit dosage, being adapted so as to obtain:
a relative quick in vitro release of the NSAID substance from the first fraction of quick release multiple-units, as measured by the dissolution method II defined herein,
an extended in vitro release of the NSAID substance from the second fraction of extended release multiple-units relative to the in vitro release of the first fraction of the NSAID substance, as measured by the dissolution method III as defined herein, the quick release and the extended in vitro release being adapted so that the first fraction is substantially released when the release from the second fraction is initiated corresponding to at least about 50% w/w release of the NSAID substance contained in the first fraction at the time when about 5% w/w of the NSAID substance contained in the second fraction is released as measured by the dissolution method III as defined herein.
The term xe2x80x9cmodified release multiple-units compositionxe2x80x9d used in the present context is defined as the release of the drug differs from that of a traditional composition. The release rate is in other words controlled and it is possible to manipulate the release rate by means of e.g. changing the formulation parameters. The rate is often controlled in such a manner that the plasma concentration levels are maintained for the longest possible period above the therapeutic (the therapeutically active) level, but below the toxic level. However, the term xe2x80x9cmodifiedxe2x80x9d is not restricted to an extended or prolonged effect, the term xe2x80x9cmodifiedxe2x80x9d may as well cover the situation where the release rate is manipulated in such a manner that a quicker release than normally expected is obtained. Thus, in the present context the terms xe2x80x9cquickxe2x80x9d, xe2x80x9cfastxe2x80x9d and xe2x80x9cenhancedxe2x80x9d release as well as xe2x80x9ccontrolledxe2x80x9d, xe2x80x9cdelayedxe2x80x9d, xe2x80x9csustainedxe2x80x9d, xe2x80x9cprolongedxe2x80x9d, xe2x80x9cextendedxe2x80x9d and other synonyms well known to a person skilled in the art are covered by the term xe2x80x9cmodifiedxe2x80x9d.
The term modified release in the present context refers to a composition which can be coated or uncoated and prepared by using pharmaceutically acceptable excipients and/or specific procedures which separately or together are designed to modify the rate or the place at which the active ingredient or ingredients are released (Ph. Eur. 97).
The term xe2x80x9cextended releasexe2x80x9d in the present context refers to a modified release composition of which the release of the active ingredient and its subsequent absorption are prolonged in comparison with a conventional non-modified form (Commision of the European Communities).
The terms xe2x80x9cquick releasexe2x80x9d, xe2x80x9cfast releasexe2x80x9d or xe2x80x9cenhanced releasexe2x80x9d in the present context refer to a modified release composition of which the release of the active ingredient and its subsequent absorption are fast. More specifically, the terms xe2x80x9cquick releasexe2x80x9d, xe2x80x9cfast releasexe2x80x9d or xe2x80x9cenhanced releasexe2x80x9d mean that for a compositionxe2x80x94when subjected to a dissolution method II described hereinxe2x80x94at least about 50% w/w of the active substance is dissolved within the first 20 min of the test.
The term xe2x80x9cfractionxe2x80x9d of multiple units in the present context refers to a part of the multiple units of a dosage unit. One fraction will generally differ from another fraction of multiple units of the dosage unit. Even though only two fractions have been defined, it is within the scope of the invention to have more than two fractions in one dosage unit. Accordingly, the dosage unit according to the invention comprises at least two fractions.
The term xe2x80x9cdosage unitxe2x80x9d in the present context refers to one single unit, e.g. a capsule, tablet, a sachet or any other relevant dosage form known within the art. A dosage unit represents a plurality of individual units which in accordance with the general state of the art may be in the form of a capsule, a tablet, a sachet, etc.
The term xe2x80x9cbioavailabilityxe2x80x9d designates the rate and extent to which the drug is absorbed from the modified multiple-units composition.
In the present context the term xe2x80x9ctherapeutically active plasma concentration which enables dosing once or twice dailyxe2x80x9d includes the situation wherein the NSAID substance administered has been metabolised to active metabolites resulting in a therapeutic effect for the stated period. It also includes the situation wherein the NSAID substance administered is present in a periferal compartment resulting in a therapeutic effect for the stated period.
The terms xe2x80x9cNSAIDsxe2x80x9d or xe2x80x9cNSAID substancesxe2x80x9d are used herein to designate a group of drugs that belongs to non-steroid anti-inflammatory drug substances and pharmaceutically acceptable salts, prodrugs and/or complexes thereof as well as mixtures thereof.
The therapeutic classes mentioned herein are in accordance with the ATC (Anatomical Therapeutic Chemical) classification system.
In the following are given examples of active drug substances which may be incorporated in a composition according to the invention. A majority of the active drug substances mentioned are weak acids, i.e. substances which have a pKa value below about 5.5 such as, e.g., in a range of from about 3.0 to about 5.5 or in a range of from about 4.0 to about 5.0. In this connection it can be mentioned that the pKa value for lornoxicam is about 4.7, for naproxen about 4.2, for indometacin about 4.5 and for acetylsalicylic acid about 3.5. When such substances which have a pKa value of between about 3.0 to about 5.5 is employed in the composition, the present inventors have found that the first fraction should be in the form of uncoated multiple-units as the coating or the manufacture of the units to a form suitable for application of a coating seem to have a retarding effect on the release rate of the active drug substance from the first fraction (see the experimental section). Moreover, active drug substances like those mentioned above (i.e. weak acids having a pKa value of at the most about 5.5 or about 5.0) generally have a poor solubility in media having a pH below the pKa value; as an example the solubility of lornoxicam at a pH corresponding to 0.1 N HCl is less than about 1 mg/100 ml at room temperature and active drug substances like acetylsalicylic acid, indometacin and naproxen are regarded as substances which are practically insoluble in water and 0.1 N HCl at room temperature. From the discussion relating to solubility and availability of the active drug substance in order to get access to the circulatory system it is should be appreciated that the release (dissolution) of the active drug substance from the first fraction should be quick under acidic conditions, e.g., in 0.1 N HCl even if the active drug substance has a very low solubility in this medium. First fractions containing such active drug substances are generally not in the form of coated multiple-units in compositions according to the invention (cf. the discussion above).
However, when the active drug substance incorporated in a composition according to the invention has a pKa value of at least about 5.0 such as at least about 5.5 the multiple-units of the invention may as well be in the form of coated multiple-units such as, e.g., coated pellet cores.
The first fraction is normally uncoated when the NSAID substance has a solubility in 0.1 N hydrochloric acid at room temperature of at the most about 0.5% w/v such as, e.g. at the most about 0.1% w/v, at the most about 0.05% w/v, at the most about 0.03% w/v, at the most about 0.01% w/w, at the most about 0.007% w/v, at the most about 0.005% w/v, at the most about 0.003% w/v, at the most about 0.002% w/v or at the most about 0.001% w/v.
The first fraction may be coated when the NSAID substance has a solubility in 0.1 N hydrochloric acid at room temperature of at least about 0.1% w/v such as e.g. at least about 0.5% w/v or at least about 1% w/v.
Relevant examples of NSAID substances suitable for use in compositions according to the invention are:
aminoarylcarboxylic acid derivatives like e.g. enfenamic acid, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, morniflumate, niflumic acid, and tolfenamic acid,
arylacetic acid derivatives like e.g. aceclofenac, acemetacin, amfenac, bromfenac, cimmetacin, diclofenac, etodolac, fentiazac, glucametacin, indomethacin, lonazolac, metiavinic acid, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, and zomepirac,
arylcarboxylic acids like e.g. ketorolac and tinoridine,
arylpropionic acid derivatives like e.g. alminoprofen, bermoprofen, carprofen, dexibuprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, protizinic acid, and tiaprofenic acid,
pyrazoles like e.g. epirizole,
pyrazolones like e.g. benzpiperylon, mofebutazone, oxyphenbutazone, phenylbutazone, and ramifenazone,
salicylic acid derivatives like e.g. acetaminosalol, acetylsalicylic acid, benorylate, eterisalate, fendosal, imidazole salicylate, lysine acetylsalicylate, morpholine salicylate, parsalmide, salamidacetic acid and salsalate,
thiazinecarboxamides like a.o. ampiroxicam, droxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam,
others like bucillamine, bucolome, bumadizon, diferenpiramide, ditazol, emorfazone, nabumetone, nimesulide, proquazone and piroxicam (e.g. in the form of a betacyclodextrin complex).
From a market point especially the following NSAIDs are interesting: lornoxicam, diclofenac, nimesulide, ibuprofen, piroxicam, piroxicam (betacyclodextrin), naproxen, ketoprofen, tenoxicam, aceclofenac, indometacin, nabumetone, acemetacin, morniflumate, meloxicam, flurbiprofen, tiaprofenic acid, proglumetacin, mefenamic, acid, fenbufen, etodolac, tolfenamic acid, sulindac, phenylbutazone, fenoprofen, tolmetin, acetylsalicylic acid, dexibuprofen and pharmaceutically acceptable salts, complexes and/or prodrugs and mixtures thereof.
Other relevant active drug substances are COX-2 (COX is an abbreviation for cyclooxygenase) inhibitors like e.g. celecosib and flosulide.
At present, the most preferred drug substance is lornoxicam and pharmaceutic ally acceptable salts, complexes and prodrugs thereof. Lornoxicam may be present in a composition according to the invention as the sole drug substance or in combination with other drug substances.
The modified release oral dosage form of the present invention preferably includes an NSAID substance as the therapeutically active ingredient in an amount corresponding to from 1 to about 1600 mg of by weight. Alternatively, the dosage form may contain molar equivalent amount s of pharmaceutically acceptable salts thereof. The dosage form contains an appropriate amount to provide a substantially equivalent therapeutic effect.
A composition according to the invention may contain a further active drug substance. Relevant substances in this context are e.g. antidepressants, opioids, prostaglandine analogs (e.g. misoprostol), glucocorticosteroids, cytostatics (e.g. methotrexate), H2 receptor antagonists (e.g. cimetidine, ranitidine), proton pump inhibitors (e.g. pantoprazole, omeprazole, lansoprazole), antacids, acetaminophen (paracetamol), penicillamine, sulfasalazine and/or auranorfin.
The term xe2x80x9cantidepressantxe2x80x9d used in the present context includes tricyclic antidepressants as well as other antidepressants and mixtures thereof. Pharmaceutically acceptable salts and/or complexes of antidepressant are also within the definition of antidepressant. Thus, the term xe2x80x9cantidepressantxe2x80x9d is used here to designate a group of drugs that have, to varying degrees, antidepressive properties and/or suitable properties with respect to alleviation or treatment of neurogenic pain and/or phantom pain. In the present context the term xe2x80x9cantidepressantxe2x80x9d encompasses drug substances mainly from the therapeutic class NO6 or from the following drug classification: Psychoanaleptics excluding antiobesity preparations; anti-depressants/thymoanaleptics including substances used in the treatment of endogenous and exogenous depression such as, e.g., imipramine, nortriptyline, amitriptyline, oxipramol and MAO-inhibiting substances; lithium; combinations of drugs with ataractics; psychostimulants including drugs which increase the psychic and physical performance and which have a fatigue depressing, stimulating effect such as, e.g., fentyllines, fencamfamine, methylphenidate, amphetamines; pyscholeptic-psychoanaleptic combinations; nootropics [which are a class of psychoactive drugs which are claimed to have a selective action on integrative functions of the CNS. Their action is alleged to be particularly associated with intellectual function, learning and memory. Nootropics include preparations containing substances such as piracetam, pyritinol, pyrisuccideanol maleate, meclofenoxate, cyprodenate and their combinations with other substances, excluding those products with a vasodilatory action (see the therapeutic class CO4A). Combinations with cardiac glycosides are classified in the therapeutic class CO1A.]; and neurotonics and other miscellaneous products including products which are not classified above such as single or combination products containing bisibutiamin, deanol and derivatives, GABA, GABOB, N-acetyl asparaginic acid glutaminic acid and salts, kavain, phospholipid, succinodinitrate.
The presently most interesting drug substances belong to the tricyclic antidepressants. Relevant examples of antidepressants are: tricyclic antidepressants such as, e.g. dibenzazepine derivatives like carpipramine, clomipramine, desipramine, imipramine, imipraminoxide, imipramine pamoate, lofepramine, metapramine, opipramol, quinupramine, trimipramine; dibenzocycloheptene derivatives like amitriptyline, amitriptyline and chlordiazepoxide, amitriptyline and medazepram, amitriptyline and pridinol, amitriptyline and perphenazine, amitriptylinoxide, butriptyline, cyclobenzaprine, demexiptiline, nortriptyline, nortriptyline and diazepam, nortriptyline and perphenazine, nortriptyline and fluphenazine, nortriptyline and flupentixol, noxiptilin, protriptyline; dibenzoxepine derivatives like doxepin; and other tricyclic anti-depressants like adinazolam, amoxapine, dibenzepin, dimetacrine, dosulepin, dosulepin and diazepam, dothiepin, fluacizine (fluoracyzine, toracizin), iprindole, maprotiline, melitracen, melitracene and flupentixol, pizotyline, propizepine, and tianeptine; other antidepressants like 5-hydroxytryptophan, ademetionine, amfebutamone, amfebutamone hydrochloride, amineptine, amineptine hydrochloride, amisulpride, fluoxetine hydrochloride, fluoxetine, hypericin, lithium carbonate, sertraline hydrochloride, sertraline, St John""s wort dry extract, trimipramine maleate, citalopram, citalopram hydrobromide, clomipramine chloride, clomipramine hydrochloride, d-phenylalanine, demexiptiline, demexiptiline hydrochloride, dimethacrine tartrate, dothiepin, dothiepin hydrochloride, doxepin, fluphenazine hydrochloride, fluvoxamine, fluvoxamine hydrogen maleate, fluvoxamine maleate, ginkgo biloba, indalpine, isocarboxazide, johanniskrauttrockenestrakt, 1-tryptophan, lithium citrate, lithium sulfate, lofepramine, maprotiline, maprotiline hydrochloride, maprotiline mesilate, medifoxamine, metaprimine fumarate, mianserin, moclobemide, nitroxazepine hydrochloride, nomifensine, nomifensine maleate, nomifensin hydrogenmaleat, oxitriptan, paroxetine, paraoxetine hydrochloride, pheneizine, pheneizine sulfate, piracetam, pirlindole, pivagabine, prolintane hydrochloride, propizepine hydrochloride, protriptyline hydrochloride, quinupramine, remoxipride hydrochloride, rubidium chloride, setiptiline maleate, tianeptine sodium, trazodone hydrochloride, venlafaxine hydrochloride, maprotiline, toloxatone, tranylcypromine, trazodone, trazodone hydrochloride, viloxazine, viloxazine hydrochloride,zimelidine, zimelidine dihydrochloride.
At present, the most interesting drug substances for use in a composition according to the invention are amitriptyline and/or imipramine and pharmaceutically acceptable salts, complexes and prodrugs thereof. Amitriptyline and/or imipramine may be present in a composition according to the present invention either as the sole drug substance or in combination with other drug substances. Amitriptyline is a very interesting drug candidate with respect to preventing and/or treating neurogenic pains and phantom pains.
The term xe2x80x9copioidxe2x80x9d is used here to designate a group of drugs that are, to varying degrees, opium- or morphine-like in their properties. The term includes natural and synthetic opioids as well as active metabolites such as morphine-6-glucuronide and morphine-3-glucuronide, and mixtures of opioids. Pharmaceutically acceptable salts and/or complexes of opioids are also within the definition of opioids.
Further relevant examples of opioids for use in compositions according to the invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocondone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicormorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, salts thereof, mixtures of any of the foregoing, mixed xcexc-agonists/antagonists, xcexc- and/or xcexa-agonists, combinations of the above, and the like.
Within the scope of the invention is of course that more than one active drug substance may be present in a composition, e.g. more than one NSAID substance and/or drug substances within the same or different therapeutic classes. Specific relevant therapeutic classes are MO1A (NSAIDs), RO5D, NO2 (analgesics), N2A (opioids) and N2B (non-narcotic analgesics).
In one embodiment of the present invention, the first fraction of multiple units comprises an amount of an NSAID substance corresponding to from about 50% to about 5% (between 1/2 and 1/20) of the daily dosage. In patients which are satisfactorily treated on 2-3 daily dosages of a conventional non-sustained formulation, the first fraction may in one example contain an amount of the NSAID substance corresponding to 40% of the daily dosage. The second fraction may then contain the remaining 60% of the daily dosage.
However, a preferred amount of the first fraction may comprise 30% of the daily dosage and the second fraction 70% of the daily dosage.
In another embodiment of the present invention, the first fraction of multiple units comprises an amount of an NSAID substance corresponding to the amount of the NSAID substance necessary for obtaining a therapeutic effect upon a first single oral dose of a conventional non-sustained formulation of the NSAID substance.
First Fraction
As described above, the formulation of the first fraction depends on the specific active drug substance to be incorporated. If the solubility at room temperature in 0.1 N HCl is low and the pKa value is below about 5.5. or 5.0, then the first fraction is in the form of uncoated multiple-units. A very suitable formulation of the first fraction has under such conditions been found to be in the form of a granulate wherein special means have been employed in order to ensure a quick release of the poor soluble active drug substance. The granulate is typically prepared by wet-granulation (a process well known for a person skilled in the art) employing as little organic solvent as possible in order to reduce any environmental and personal risk. Furthermore, the present inventors have found that incorporation of an antacid-like substance like, e.g., sodium bicarbonate (sodium hydrogencarbonate), magnesium carbonate, magnesium hydroxide, magnesium metasilicate aluminate and other alkaline substance, has a pronounced increasing effect on the release rate.
In one embodiment, the individual units of the relatively fast release fraction according to the invention will normally be a granulate having a size (average diameter) of at the most about 250 xcexcm such as, e.g. at the most about 240 xcexcm, at the most about 230 xcexcm, at the most about 220 xcexcm, at the most abut 210 xcexcm, at the most about 200 xcexcm, at the most about 190 xcexcm, at the most about 180 xcexcm, at the most about 175 xcexcm, at the most about 150 xcexcm, at the most about 125 xcexcm, at the most about 100 xcexcm, at the most about 90 xcexcm or at the most about 80 xcexcm.
As described above, the first fraction may also be in the form of coated multiple-units such as coated pellets provided that the pK, of the active drug substance is at least about 5.0 or 5.5. From the experimental section inter alia it appears that such coated cores may have the same coating as the coating of the second fraction, but the thickness of the coating differs in such a manner that the coating of the first fraction is much thinner than that of the second fraction. For further details with respect to coating see below.
Second Fraction
The individual units of the extended release fraction according to the invention will normally be pellets or beads having a size (average diameter) of from about 0.1 to 2 mm. The most preferred pellet size is from 0.5 to 0.8 mm. The pellets or beads comprise a combination of active substance, the NSAID substance and excipients.
When the pellets or beads are not coated, the combination of the active substance and the excipients is referred to as a core.
In the present context, the term xe2x80x9ccores which are cross-sectionally substantially homogeneousxe2x80x9d designates cores in which the active substance is not confined to an exterior layer on the core body, in other words normally cores which, through the cross-section of the core body, contain substantially the same type of composition comprising minor particles containing active substance, in contrast to the non-pareil type of cores which each consists of an excipient body with active substance applied to its surface. From this definition, it will be understood that the cores which are cross-sectionally substantially homogeneous will normally consist of a mixture of active substance with excipient(s), this mixture will not necessarily be qualitatively or quantitatively homogeneous through the total cross-sectional area of the core but may show, e.g., a concentration gradient of the NSAID substance or they may consist substantially solely of NSAID substance. In the following specification and claims, such cores which are cross-sectionally substantially homogeneous will, for the sake of brevity, often simply be designated xe2x80x9ccoresxe2x80x9d.
It is contemplated that the core comprising the NSAID substance in a substantially homogeneous form provides a more reproducible release of the active ingredient than compared to e.g. particles in which the active ingredient forms part of the coating.
It should, however, be understood that the invention is not limited to pellet formulation containing the above-mentioned cores; in principle, the type of cores can be any kind such as, e.g. matrices, non-pareil cores as well.
It is preferred that the release profile of the core of the individual unit is substantially non-limiting with respect to the desired release of the coated pellet, e.g. that the core itself provides at least about 90% w/w such as, e.g., at least about 95% w/w, at least about 97% w/w, at least about 98% such as about 100% release within 1 hour, measured in the in vitro dissolution test described in the Examples. However, pellet cores showing a slower release of the active substance are still within the scope of the invention.
The oral pharmaceutical modified release multiple-units formulation according to the invention will typically be a capsule containing a multiplicity of the units, typically more than 100, a sachet containing a multiplicity of the units, typically more than 1000, or a tablet made from a multiplicity of the units, typically more than 100, in such a manner that the tablet will disintegrate substantially immediately upon ingestion in the stomach into a multiplicity of individual units which are distributed freely throughout the gastrointestinal tract.
In the present context the term xe2x80x9conce dailyxe2x80x9d/xe2x80x9conce-a-dayxe2x80x9d is intended to mean that it is only necessary to administer the pharmaceutical formulation once a day in order to obtain a suitable therapeutic and/or prophylactic response; however, any administration may comprise co-administration of more than one dosage unit, such as, e.g., 2-4 dosage units if the amount of active substance required may not be formulated in only one composition unit or if a composition unit of a minor size is preferred.
In agreement with the above-mentioned definition of xe2x80x9conce dailyxe2x80x9d/xe2x80x9conce-a-dayxe2x80x9d, xe2x80x9ctwice dailyxe2x80x9d/xe2x80x9ctwice-a-dayxe2x80x9d is supposed to mean that it is only necessary to administer the pharmaceutical formulation at the most twice a day in order to obtain a suitable therapeutic and/or prophylactic response in the patient.
Irrespective of the above-mentioned definitions of xe2x80x9concexe2x80x9d and xe2x80x9ctwicexe2x80x9d daily, a dosage unit constructed to deliver the active ingredient after only one daily administration is preferred. However, due to individual circumstances some patients may need a new dosage after e.g. 12 or 18 hours if the patient e.g. has an abnormal absorption or bowel transit time. If the individual has a relatively fast bowel transit time, some of the active ingredient may be excreted before the full dosage is released, or may be released in the colon from which the absorption may be decreased.
A multiple unit pharmaceutical composition according to the present invention is preferably formed as a unit dosage form which upon oral administration disintegrates into a multiplicity of individual units. The dosage unit form is preferably a solid dosage unit form such as, e.g., a tablet, a capsule, or a sachet, especially in the form of capsules.
The actual load of the NSAID substance in a pharmaceutical composition according to the invention, i.e. the concentration in % w/w of the NSAID substance calculated on the total weight of the multiple units, may depend on the particular NSAID substance employed in the formulation. The formulation principle employed in the present invention is very flexible. As an example it can be mentioned that compositions can be designed so that the load of the NSAID substance in the individual multiple units of the two fractions and the content of the two fractions for one dosage unit comprising e.g. 10 mg of NSAID substance is identical with another dosage unit comprising e.g. 100 mg, the release profile for each of the dosages will be identical. Consequently, an individual total dosage can be administered to the patient by combining the relevant dosage units e.g. selected from a series of 4, 8, 12, 16, 24 and 32 mg of the NSAID substance without altering the overall release profile of the total amount of the NSAID substance administered.
The compositions mentioned above may be prepared by conventional methods known in the art. The invention also relates to a method for preparing an oral pharmaceutical modified release multiple-units composition.
In a further embodiment, the invention relates to a method for preparing an oral pharmaceutical modified release multiple-units formulation in which
a) individual units containing an active substance are coated with an inner film-coating mixture (xe2x80x9cthe inner coatxe2x80x9d) comprising a film-forming substance,
b) the thus coated units are optionally provided with a first outer film layer comprising e.g. a stabilizing agent (xe2x80x9cthe middle coatxe2x80x9d),
c) the thus coated units of the second fraction are optionally provided with a second outer film layer comprising a film-forming agent (xe2x80x9cthe outer coatxe2x80x9d),
d) a mixture of individual units of the first and second fraction are formulated in a dosage form in the desired ratio of the two fractions.
In general, the inner coating is applied in an amount corrsponding to 2-20% w/w. The middle coating, if present, is applied in an amount corresponding to about 4% w/w of the uncoated units and the outer coat is applied in an amount corresponding to about 1-2% w/w of the uncoated units.
The film-forming agent of step c) may be so selected that adhesion between the units is prevented at elevated temperatures, the coated units are then subsequently heated to a temperature above 40xc2x0 C., preferably not above 65-75xc2x0 C., and thereby a continuous phase is formed in the inner film layer in homogeneous admixture with the film-forming substance. In some cases, this curing process may also take place before the outer coating layer may be applied.
The modified release coating is applied on the multiple units from a solution and/or suspension preferably in an aqueous solvent, but an organic coating composition may also be applied.
Examples of film-forming agents which are suitable for use in accordance with the present invention are agents selected from the group consisting of cellulose derivatives such as, e.g., ethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose valerate, cellulose acetate propionate; acrylic polymers such as, e.g., polymethyl methacrylate; vinyl polymers such as, e.g., polyvinyl acetate, polyvinyl formal, polyvinyl butyryl, vinyl chloride-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, vinyl chloride-propylene-vinyl acetate copolymer; silicon polymers such as, e.g., ladder polymer of sesquiphenyl siloxane, and colloidal silica; polycarbonate; polystyrene; polyester; coumarone-indene polymer; polybutadiene; and other high molecular synthetic polymers.
In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
In one preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the tradename Eudragit(copyright). In further preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the tradenames Eudragit(copyright) RL 30 D and Eudragit(copyright) RS 30 D, respectively. Eudragit(copyright) RL 30 D and Eudragit(copyright) RS 30 D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit(copyright) RL 30 D and 1:40 in Eudragit(copyright) RS 30 D. Eudragit(copyright) RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids. The Eudragit(copyright) RL/RS dispersions may be mixed together in any desired ratio in order to ultimately obtain a modified release formulation having a desirable dissolution profile. The most desirable modified release formulations may be obtained from a retardant coating based on Eudragit(copyright) NE 30 D, which is a neutral resin having a molecular weight of 800,000.
The amount of coating applied is adapted so as to obtain a predetermined dissolution characteristic of the fraction of the composition. The percentage by weight of the modified release coating on the individual pellet will, for the fraction providing the extended duration of effect of the NSAID substance, be at the most about 20% w/w on an average, such as, e.g. about 15% w/w, about 12% w/w, preferably at the most about 10% w/w on an average, more preferred in the range of about 3% to 6% w/w on an average, based on the weight of the uncoated individual pellet. The amount of coating applied depends on the predetermined dissolution characteristics of the particular core composition and the desired release profile of the fraction.
However, the amount of coating applied should also be adapted so that there will be no rupturing problems.
The coating may be admixed with various excipients such as plasticizers, anti-adhesives such as, e.g., colloidal silicium dioxide, inert fillers, and pigments in a manner known per se.
Tackiness of the water-dispersible film-forming substances may be overcome by simply incorporating an anti-adhesive in the coating. The anti-adhesive is preferably a finely divided, substantially insoluble, pharmaceutically acceptable non-wetting powder having anti-adhesive properties in the coating. Examples of anti-adhesives are metallic stearates such as magnesium stearate or calcium stearate, microcrystalline cellulose, or mineral substances such as calcite, substantially water-insoluble calcium phosphates or substantially water-insoluble calcium sulphates, colloidal silica, titanium dioxide, barium sulphates, hydrogenated aluminium silicates, hydrous aluminium potassium silicates and talc. The preferred anti-adhesive is talc. The anti-adhesive or mixture of anti-adhesives is preferably incorporated in the coating in an amount of about 0.1-70% by weight, in particular about 1-60% by weight, and preferably about 8-50% by weight of the inner film layer. By selecting a small particle size of the talc, a larger surface area is obtained; the consequent higher anti-adhesive effect makes it possible to incorporate smaller amounts of specific anti-adhesives.
The individual modified release coated multiple-units may further comprise a middle coating between the xe2x80x9cinner coatxe2x80x9d and the xe2x80x9couter coatxe2x80x9d. Such coating may be adapted to stabilize the controlled release coated multiple-units and to prevent undesired changes of the release profile of each coated unit. Accordingly, the middle lacquer or coating may contribute to stability of the release profile of the dosage unit. Accordingly, the multiple units may further comprise an outer film layer.
In one aspect, the outer second layer comprises a water-based film-forming agent which prevents adhesion between the units at elevated temperatures and imparts flowability to the units, the water-based film-forming agent being anti-adhesive at temperatures above about 40xc2x0 C., especially temperatures above about 50xc2x0 C., such as a temperature between about 60xc2x0 C. and about 120xc2x0 C., and being selected from diffusion coating materials such as ethylcellulose or enteric coating materials such as anionic poly(meth)acrylic acid esters, hydroxypropylmethylcellulosephthalate, celluloseacetatephthalate, polyvinylacetatephthalate, polyvinylacetate phthalate-crotonic acid copolymerisates, or mixtures thereof, or water-soluble coating materials such as water-soluble cellulose derivatives, e.g. hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, propylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, hydroxymethylcellulose, carboxymethylethylcellulose, methylhydroxypropylcellulose or hydroxypropylmethylcellulose.
Examples of plasticizers for use in accordance with the present invention include triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyloxalate, diethylmalate, diethylmaleate, diethylfumarate, diethylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacetate, triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol, propyleneglycol, 1,2-propyleneglycol, dibutylsebacate, diethylsebacate and mixtures thereof. The plasticizer is normally incorporated in an amount of less than 10% by weight, calculated on the dry matter content of the coating composition.
Apart from the active drug substance in the multiple units, the pharmaceutical composition according to the invention may further comprise pharmaceutically acceptable excipients.
In the present context, the term xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d is intended to denote any material which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. A pharmaceutically acceptable excipient may be added to the active drug substance with the purpose of making it possible to obtain a pharmaceutical formulation which has acceptable technical properties. Although a pharmaceutically acceptable excipient may have some influence on the release of the active drug substance, materials useful for obtaining modified release are not included in this definition.
Filler/diluents/binders may be incorporated such as sucrose, sorbitol, mannitol, lactose (e.g., spray-dried lactose, xcex1-lactose, xcex2-lactose, Tablettose(copyright), various grades of Pharmatose(copyright), Microtose or Fast-Floc(copyright)), microcrystalline cellulose (e.g., various grades of Avicel(copyright), such as Avicel(copyright) PH101, Avicel(copyright) PH102 or Avicel(copyright) PH105, Elcema(copyright) P100, Emcocel(copyright), Vivacel(copyright), Ming Tai(copyright) and Solka-Floc(copyright)), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH 22, LH 21, LH 20, LH 32, LH 31, LH30), dextrins, maltodextrins (e.g. Lodex(copyright) 5 and Lodex(copyright) 10), starches or modified starches (including potato starch, maize starch and rice starch), sodium chloride, sodium phosphate, calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate), calcium sulfate, calcium carbonate. In pharmaceutical formulations according to the present invention, especially microcrystalline cellulose, L-hydroxypropylcellulose, dextrins, maltodextrins, starches and modified starches have proved to be well suited.
Disintegrants may be used such as cellulose derivatives, including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol(copyright)); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon(copyright) CL, Polyvidon(copyright) CL-M, Kollidon(copyright) CL, Polyplasdone(copyright) XL, Polyplasdone(copyright) XL-10); sodium carboxymethyl starch (e.g. Primogel(copyright) and Explotab(copyright)).
Surfactants may be employed such as nonionic (e.g., polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitane monoisostearate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan tri oleate, glyceryl monooleate and polyvinylalkohol), anionic (e.g., docusate sodium and sodium lauryl sulphate) and cationic (e.g, benzalkonium chloride, benzethonium chloride and cetrimide) or mixtures thereof.
Other appropriate pharmaceutically acceptable excipients may include colorants, flavouring agents, and buffering agents.
In the following examples, the invention is further disclosed.